Alternative First-line Regimens Research Articles

Molecular Evaluation of HIV-1 HAART Efficacy, Comparison of TDF+3TC+EFV and AZT+3TC+NVP Regimens

Context: The UNAIDS goal of ending the HIV epidemic by 2030 will be achieved primarily through the success of the three “95s” by 2030, and in particular the third “95 », which consists of achieving an undetectable viral load thanks to effective antiretroviral treatment. Achieving and maintaining viral suppression is the goal of ART and a good knowledge of the effectiveness of triple ARV therapies can help national HIV programs. Thus, the objective of this study was to evaluate and compare the effectiveness of the two ARTs, Tenovofir + Lamivudine +Efavirenz (TDF+3TC+EFV) and Zidovudine+Lamivudine+ Efavirenz (AZT+3TC+NVP) in their abilities to make the plasma viral load of HIV+ patients under treatment undetectable. 
 
 Material and method: This is a retrospective study of the management of HIV-1 seropositive patients, followed at the Military Hospital of Ouakam (HMO) Molecular Biology laboratory from 2014 to 2021. The main criterion for evaluating the effectiveness of the treatment was the proportions of patients whose Viral load values were undetectable, VL< 50 copies/ml depending on duration of antiretroviral therapy (ART). Plasma viral load tests were carried out on Abbott Real Time HIV-1® (m2000sp/rt) and COBAS®AmpliPrep/COBAS®TaqMan® (Roche) version 2.0. Variables with p<0.05 were considered statistically significant for all comparisons between groups.
 
 Results: 3,335 patients met the inclusion criteria, including 2,078 on TDF+3TC+EFV, 445 on AZT+3TC+NVP and 812 were excluded due to death, transfer or loss to follow-up. At 6 months of ART, VL was undetectable in 7.3% of patients on TDF+3TC+EFV and 6.7% of patients on AZT+3TC+NVP (P=0.67). 78.2% versus 73.4% of patients had an undetectable VL respectively for TDF+3TC+EFV and AZT+3TC+NVP at 12 months of ART (p=0.03). TDF+3TC+EFV had significantly higher virological success rates than AZT+3TC+NVP (85.7% versus 80.2%) and virological failure (VL>1000 copies/ml) was significantly greater in patients taking AZT+3TC+NVP (13% versus 7.2%) after 18 months (P=0.001). Gender and age had a significant relationship in treatment success.
 
 Conclusion: TDF+3TC+EFV was superior in terms of virological suppression at the end of the study period. These results support the WHO recommendation to use TDF+3TD+EFV as an alternative first-line regimen.

Pharmacoeconomic analysis of cost-effectiveness when using obinutuzumab (Gazyva ® drug) in treating chronic lymphocytic leukemia in Ukraine

Background. Chronic lymphocytic leukemia (CLL) is the most common type of leukemia. Annual incidence rate of CLL is 2 to 6 per 100000 population. CLL is currently a disease which leads to significant social and financial costs. CLL remains an incurable disease up to this date. However, at the moment there is a bunch of drugs available on the pharmaceutical market, which can substantially elongate progression-free survival, increase duration, and improve the patients’ quality of life. One of such drugs is obinutuzumab. Positive evaluation findings of economic feasibility of using obinutuzumab in elderly patients with CLL have been received in some countries of the European Union, but under the conditions of healthcare of Ukraine pharmacoeconomic analysis of obinutuzumab use in the treatment of CLL has not been performed.
 The purpose of the work is to determine economic feasibility of using obinutuzumab (Gazyva® drug) under the conditions of healthcare system of Ukraine for the treatment of chronic lymphocytic leukemia in patients who did not receive treatment earlier.
 Materials and methods. An analysis using the Markov analysis model was performed, and it allowed the comparison between life years gained (LYG) and quality adjusted life years (QALY) to be made, which can be obtained when using alternative regimens (O+Clb or R+Clb) and expenditures on these regiments in treating patients with CLL. The analysis modelling was performed on the basis of the results of international randomized multicenter open phase III clinical trial of CLL11.
 Results. The results of Markov modelling have shown that O+Clb treatment regimen, which consists of obinutuzumab and chlorambucil, provides every patient with CLL with additional 0,1 LYG on average over a period of three years compared to R+Clb regimen. The average lifespan of the patients in whom the disease did not progress was higher in O+Clb group than in R+Clb group by more than a year – 51,2 and 38,1 months respectively. O+Clb regimen not only increases lifespan, but also improves life quality. The patients of R+Clb group have additional 0,14 QALY during the analyzed period compared to O+Clb group. The calculation of expenses on CLL treatment with consideration for time horizon of 3 years has shown that using obinutuzumab in the first line of treatment was almost twice as expensive as the alternative first-line regimen, provided that original pharmaceutical drugs were used. At the same time, due to the greater effectiveness, the high cost of the regimen with obinutuzumab is compensated by reduction in expenses on the second line of chemotherapy. The cost saving on the second line covers the cost difference of the first line of therapy when using obinutuzumab. When using original, as well as generic chemotherapeutic drugs, O+Clb (obinutuzumab + chlorambucil) regimen as a first-line therapy of patients with CLL provides the higher level of effectiveness at smaller cost. Conclusions. The available data of randomized control trials to this date are indicative of high clinical effectiveness of first-line therapy with the use of obinutuzumab + chlorambucil regimen in the patients with CLL. This regimen allows progression-free survival to be substantially elongated. It also increases the number of life years gained and improves the quality of life. Markov modelling shows that obinutuzumab + chlorambucil regimen compared to rituximab + chlorambucil regimen requires bigger expenses as a first-line therapy of the patients with CLL. At the same time, due to the greater effectiveness and longer progression-free survival, this regimen allows the amount of expenses on the next lines of therapy in the patients with CLL to be reduced, consequently total expenses on the treatment of the patients with CLL are also reduced. Pharmacoeconomic analysis based on the Markov analysis model and calculations by the «cost-effectiveness» and «cost-utility» methods allow obinutuzumab + chlorambucil regimen to be considered dominant in comparison with rituximab + chlorambucil regimen as a first-line therapy of the patients with CLL (provided that original pharmaceutical drugs are used).

TCOG T5217 trial: A phase II randomized study of SLOG versus modified FOLFIRINOX as the first-line treatment in locally advanced or metastatic pancreatic ductal adenocarcinoma.

4143 Background: The triplet regimen of S-1, leucovorin, oxaliplatin and gemcitabine (SLOG) has shown promising efficacy for metastatic pancreatic ductal adenocarcinoma (PDAC) in our previous study. Current multicenter randomized, phase II study compared the efficacy and safety of SLOG versus modified FOLFIRINOX (mFOLFIRINOX) in patients with advanced/metastatic PDAC. Methods: Patients with chemo-naïve, histologically confirmed advanced/metastatic PDAC, were randomly assigned to either SLOG (gemcitabine 800 mg/m2, fixed-rate infusion and oxaliplatin 85 mg/m2 on day 1, plus daily 40/50/60 mg of S-1 based on BSA and 30 mg of oral leucovorin, twice daily, on days 1-7, every 2 weeks) or mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2 and leucovorin 400 mg/m2 on day 1 plus 5-FU 2400 mg/m2 for 46 hrs, every 2 weeks). Patients were stratified according to disease extent, ECOG PS and primary tumor location. The primary endpoint was 6-month progression-free survival (PFS) rate. The secondary endpoints were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS) and safety profile. Tumor response was assessed by CT/MRI every 8 weeks according to RECIST v1.1. As an exploratory trial, 130 (65 per arm) patients were estimated to detect a two-sided 15% difference in 6-month PFS (60% in SLOG and 45% in mFOLFIRINOX) with a significant level of α = 0.1 and β = 0.25. Results: Between March 2018 and October 2019, 130 patients were accrued. One patient who was assigned to mFOLFIRINOX arm didn’t receive assigned treatment. Of them, 62.3% were male, 45.4% were ECOG PS0, 81.5% had metastatic diseases, and 16.9% had prior surgery. The 6-month PFS rate was 55.4% in SLOG arm (n = 65) and 50% in mFOLFIRINOX arm (n = 64) (p = 0.850). The ORR and DCR in the SLOG and the mFOLFIRINOX arms were 40% versus 26.6% (p = 0.135) and 76.2% versus 71.9% (p = 0.550), respectively. The median PFS was 7.5 months in SLOG arm and 6.5 months in mFOLFIRINOX arm (p = 0.395); while the median OS was 12.9 months in SLOG arm and 12.1 months in mFOLFIRINOX arm (p = 0.88). Ten patients underwent conversion surgery, of whom 7 had SLOG and 3 had mFOLFIRINOX. The incidence of grade 3/4 neutropenia was significantly higher in mFOLFIRINOX arm (53.2% vs. 16.9% in SLOG arm, p < 0.0001). Conclusions: SLOG could achieve comparable but numerically better ORR, and median PFS and OS as compared to mFOLFIRINOX in patients of advanced PDAC. SLOG can be an alternative first-line regimen for advanced PDAC patients. Clinical trial information: NCT03443492.

"Open Sesame?": Biomarker Status of the Human Equilibrative Nucleoside Transporter-1 and Molecular Mechanisms Influencing its Expression and Activity in the Uptake and Cytotoxicity of Gemcitabine in Pancreatic Cancer.

Simple SummaryDespite the enormous advance in biomarker discovery, many potential biomarkers of drug activity are unable to satisfy the clinical need due to inadequate sensitivity and specificity. The nucleoside transporter hENT-1 has been studied as a potential biomarker to predict the effect of the widely used anticancer drug gemcitabine in pancreatic cancer. However, several studies showed controversial results regarding the predictive value of hENT-1, prompting new analyses with larger cohorts of patients and standardized methodologies. Improved insights on molecular mechanisms underlying hENT-1 expression and activity should also help in the identification of subsets of patients who are more likely to benefit from specific treatments and improve their clinical outcome. The establishment of such biomarker is especially valuable in pancreatic cancer, which is frequently characterized by complex disease biology and high mortality.Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as an upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free status and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. This commentary aims to critically discuss this analysis and lists molecular factors influencing hENT-1 expression. Improved knowledge on these factors should help the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.

Drug resistance from preferred antiretroviral regimens for HIV infection in South Africa: A modeling study.

BackgroundTenofovir-containing regimens comprise the preferred first-line antiretroviral therapy (ART) in many countries including South Africa, where utilization of second-line regimens is limited. Considerable HIV drug resistance has occurred among persons failing tenofovir-containing first-line ART. We evaluated drug resistance at the population level using mathematical modeling.SettingHeterosexual HIV epidemic in KwaZulu-Natal, South Africa.MethodsWe constructed a stochastic individual-based model and simulated scenarios of ART implementation, either CD4-based (threshold < 500 cells/mL) or Fast-track (81% coverage by 2020), with consideration of major drug-associated mutations (M184V, K65R and non-nucleoside reverse transcriptase inhibitor (NNRTI)). Using base case and uncertainty analyses, we assessed (majority) drug resistance levels.ResultsBy 2030, the median total resistance (proportion of HIV-infected persons with drug resistance) is predicted to reach 31.4% (interquartile range (IQR): 16.5%-50.2%) with CD4-based ART, decreasing to 14.5% (IQR: 7.7%-25.8%) with Fast-track implementation. In both scenarios, we find comparably high prevalence (~80%) of acquired NNRTI-associated, M184V and K65R mutations. Over 48% of individuals with acquired resistance harbor dual, 44% triple and 7% just single drug mutations. Drug-resistant HIV is predicted to comprise 40% (IQR: 27%-50%) of incident infections, while 70% of prevalent transmitted resistance is NNRTI-associated. At 2018, the projected total resistance is 15% (IQR: 7.5%-25%), with 18% (IQR: 13%-24%) of incident infections from transmitted drug-resistant HIV.ConclusionsWHO-recommended preferred first-line ART could lead to substantial drug resistance. Effective surveillance of HIV drug resistance and utilization of second-line as well as alternative first-line regimens is crucial.

Bridging the gap between HIV epidemiology and antiretroviral resistance evolution: Modelling the spread of resistance in South Africa.

The scale-up of antiretroviral therapy (ART) in South Africa substantially reduced AIDS-related deaths and new HIV infections. However, its success is threatened by the emergence of resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI). The MARISA (Modelling Antiretroviral drug Resistance In South Africa) model presented here aims at investigating the time trends and factors driving NNRTI resistance in South Africa. MARISA is a compartmental model that includes the key aspects of the local HIV epidemic: continuum of care, disease progression, and gender. The dynamics of NNRTI resistance emergence and transmission are then added to this framework. Model parameters are informed using data from HIV cohorts participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) and literature estimates, or fitted to UNAIDS estimates. Using this novel approach of triangulating clinical and resistance data from various sources, MARISA reproduces the time trends of HIV in South Africa in 2005–2016, with a decrease in new infections, undiagnosed individuals, and AIDS-related deaths. MARISA captures the dynamics of the spread of NNRTI resistance: high levels of acquired drug resistance (ADR, in 83% of first-line treatment failures in 2016), and increasing transmitted drug resistance (TDR, in 8.1% of ART initiators in 2016). Simulation of counter-factual scenarios reflecting alternative public health policies shows that increasing treatment coverage would have resulted in fewer new infections and deaths, at the cost of higher TDR (11.6% in 2016 for doubling the treatment rate). Conversely, improving switching to second-line treatment would have led to lower TDR (6.5% in 2016 for doubling the switching rate) and fewer new infections and deaths. Implementing drug resistance testing would have had little impact. The rapid ART scale-up and inadequate switching to second-line treatment were the key drivers of the spread of NNRTI resistance in South Africa. However, even though some interventions could have substantially reduced the level of NNRTI resistance, no policy including NNRTI-based first line regimens could have prevented this spread. Thus, by combining epidemiological data on HIV in South Africa with biological data on resistance evolution, our modelling approach identified key factors driving NNRTI resistance, highlighting the need of alternative first-line regimens.

Oral Teicoplanin as an Alternative First-Line Regimen in Clostridium difficile Infection in Elderly Patients: A Case Series.

Elderly patients are more susceptible to Clostridium difficile infections (CDIs). Despite existing guidelines, there is no specific treatment for CDI in geriatrics. Vancomycin is commonly used in the treatment of CDI. Teicoplanin is an alternative glycopeptide which recently received marketing authorization approval for CDI in Europe. Evaluate the potential interest of oral teicoplanin and assess whether such treatment could potentially become an alternative treatment in mild to severe CDIs in elderly patients. A prospective monocentric study was conducted over 10 months (from December 2015 to October 2016) in a geriatric unit (Sainte Périne, AP-HP, Paris, France). According to the remote infectious disease specialist, some hospitalized patients suffering from CDI and aged over 65 years received oral teicoplanin 200 mg twice a day (highest dose recommended). The clinical response to teicoplanin and relapses after treatment were evaluated. Patients were monitored up to 90 days after teicoplanin administration, and analyzed in non-responder imputation analysis. Eleven patients received teicoplanin among 19 CDIs during the study time period. In non-responder imputation analysis, 90.9% (n = 10) successfully responded to oral teicoplanin. The rate of relapse observed after a 90-day follow-up was 36.4%. Patients reported no drug-related adverse effects. Oral teicoplanin is a glycopeptide that could be proposed as an alternative to other recommended drugs for CDI. In our case series, teicoplanin seems to be an effective therapy as a first-line regimen for CDI in geriatrics. Such treatment has good acceptability in geriatrics, considering it can be taken orally twice a day.

Prevalence of rilpivirine resistance in people starting antiretroviral treatment in Argentina.

Rilpivirine-based regimens are now preferred or alternative first-line regimens according to many HIV treatment guidelines. Recently, a surveillance study conducted in Argentina determined that prevalence of pretreatment resistance to first-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) was 10%. The aim of this study was to analyse the prevalence of resistance mutations to newer generation NNRTIs in the population starting ART in Argentina. We analysed the prevalence of resistance mutations to rilpivirine and etravirine (according to the IAS list), obtained through a nationally representative pretreatment HIV-drug resistance (PDR) surveillance study performed in Argentina in 2014-2015. Briefly, 25 ART-dispensing sites throughout the country were randomly chosen to enrol 330 adults starting ART. Samples were processed with Trugene (Siemens)® and analysed using the Stanford algorithm. All 270 samples corresponding to participants with no prior exposure to antiretroviral drugs were included in this analysis. Median (IQR) age was 35 years (28-43); 66.7% were male; median (IQR) CD4+ T-cell count was 284 cells/mm3 (112-489). The prevalence of resistance to any antiretroviral was 16% (±5%) and prevalence of NNRTI RAMs was 13% (±4%). The prevalence of resistance to rilpivirine was 8% (±3%). Prevalence of resistance to etravirine was 4% (±3%). The most frequent mutations conferring resistance to rilpivirine were: E138A (n=6) and G190A (n=4). This PDR surveillance study showed concerning levels of HIV drug resistance (HIVDR) in Argentina, not only for first-generation NNRTIs but also to rilpivirine. In our setting, performing resistance testing would be necessary before prescription of ART even if a second-generation NNRTI-based regimen was used as first-line therapy.

Colorectal Cancer Survival Gains and Novel Treatment Regimens: A Systematic Review and Analysis.

The past 2 decades have witnessed progress in the management of metastatic colorectal cancer (mCRC) with more effective agents and better surgical, medical, and supportive care. While substantial progress has been made, much more must be achieved to prolong the lives of patients. To conduct a systematic review to ascertain what percentage of the life expectancy gain in locally advanced and mCRC over the past 2 decades is due to novel therapies vs improvements in supportive care or secular trends and to thus inform treatment development strategies. We searched Cochrane Controlled Trials Register, Medline, Embase, CancerLit, and Healthstar electronic databases for trials covering the period 1993 to 2015, scanned reference lists of articles, and searched recent conference abstracts. Ninety-six phase 3 trials and large (>50 patients) phase 2 trials in mCRC were examined. Outcomes evaluated in the experimental arms (EAs) and control arms (CAs) included overall response rate, stable disease, progression-free survival (PFS), and overall survival (OS). Over the period covered by the studies, the OS in EAs increased at a mean (95% CI) rate of 0.80 (0.67-0.93) mo/y. Importantly, OS in the CAs improved 0.63 (0.51-0.75) mo/y, reflecting in part the use of experimental regimens in subsequent studies. Chemotherapy contributed only partly to the gains in OS, given that (1) mean (95% CI) improvements in PFS were only 0.31 (0.22-0.39) mo/y in the EAs and 0.23 (0.15-0.31) mo/y in CAs; (2) gains in survival not directly attributable to the protocol were greater than gains in PFS (0.46 [0.36-0.57] mo/y in EAs and 0.39 [0.29-0.49] mo/y in CAs; and (3) effects on OS were much lower in second-line trials (median [interquartile range] response rates, 8.6% [0%-11.0%] in EAs and 7.5% [3.8%-12.8%] in CAs) compared with first-line trials (39.5% [24.0%-50.2%] for EAs and 29.4% [16.4%-39.4%] for CAs). The OS of patients with mCRC has improved gradually over the past 2 decades, with gains from chemotherapy occurring alongside gains from lead-time bias and improved locoregional approaches and supportive care. Gains from first-line therapies have been modest but consistent; however, gains from second-line therapies have been disappointing. We believe that future progress will be greater if emphasis is placed on enrolling patients in experimental trials to explore and develop alternative first-line regimens and better second-line therapies.

Less Toxic Gemcitabine-Oxaliplatin Based Induction Regimen (R-GIDIOX) Prior to Autologous SCT Produces Outcomes Similar to High-Dose Cytarabine Containing Intensive Induction Regimen in Mantle Cell Lymphoma – a Follow up Report of the Multicenter Study

Abstract Background: MCL is B-cell neoplasm diagnosed predominantly among older men. (R)CHOP-like regimens demonstrated high response rate, but the event-free survival (EFS) and overall survival (OS) are disappointingly short - 16-20 months and 3-4 years, respectively. An addition of high-dose AraC (12 g/m2) to the upfront therapy and autoSCT have significantly improved outcomes but remain feasible largely for younger and medically fit patients. Based on the activity and good tolerance of gemcitabine-oxaliplatin combinations in relapsed and refractory MCL patients, we developed an alternative first-line regimen for patients who are not candidates for R-HD-MTX-AraC (R-HMA). We presented an initial data of our pilot protocol at ASH 2012 (#2043). According to the protocol patients who had renal insufficiency and/or experience prohibitive toxicity following the first course of R-EPOCH, were assigned to receive R-EPOCH/R-GIDIOX regimen, while others were treated with R-EPOCH/R-HMA regimen. Both arms received consolidative autoSCT followed by R-maintenance. Aim: Assess toxicity and efficacy of R-DA-EPOCH/R-HMA and R-DA-EPOCH/R-GIDIOX in untreated MCL patients eligible for autoSCT. Patients and Methods: 47 untreated MCL patients from 6 centers were enrolled in prospective study between May 2008 - Sep. 2013; stage II-IV; ECOG 0-3; median age 55 years (29-64); M/F 76%/24%; MIPIb: 28% low, 33% intermediate and 39% high risk. Following 1st R-EPOCH patients were assigned to receive either R-DA-EPOCH/R-HMA or R-DA-EPOCH/R-GIDIOX regimen. In the absence of hematological toxicity gr. 4, severe infections and renal failure patients received R-HMA (R 375 mg/m2 d1, MTX 1000 mg/m2/24 hours d 2, AraC 3000 mg/m2 q 12 hrs d 3-4). Patients who experienced at least one of the complications above received R-GIDIOX (R 375 mg/m2 d 1, gemcitabine 800 mg/m2 d 2 and 5, oxaliplatin 120 mg/m2 d 3, irinotecan 100 mg/m2 d 4, dexamethasone 10 mg/m2 IV d 2-6, ifosfamide 1000 mg/m2 d 2-6). Subsequently these courses were alternating with R-DA-EPOCH in each arm of the protocol. Patients who achieved CR after the first cycle (2 courses), received additional 2 cycles, (for a total 6 courses). Patients without CR after 2 cycles of therapy received 2 more cycles, for total of 8 courses, unless they progressed on therapy. Those patients who achieved PR/CR/CRu underwent autoSCT (BEAM-R). Response the therapy was assessed by Cheson's criteria (2007). Patients with residual PET+ tumor after autoSCT were consolidated with local radiotherapy. Post-transplant R- maintenance was administered for 3 years (R-375 mg/m2 every 3 months). Patients were analyzed on an intent-to-treat basis. Results: 29/47 patients were treated on R-HMA arm (Arm1) (median 51years; MIPIb: 35,7% low, 28,6% intermediate and 35,7% high risk) and 18/47 patients were on R-GIDIOX arm (Arm2) (median 60 years; MIPIb: 16,7% low, 38,9% intermediate and 44,4% high risk). There was 1/29 induction death after first R-HMA course (acute renal failure and septic shock). 1 of 18 patients had disease progression before autoSCT in Arm2. 28/29 patients from Arm1 achieved CR/CRu (96,6%). In Arm 2 OR and CR/CRu rates were 94,4% (17/18) and 77,8% (14/18), respectively. Main non-hematological toxicity of R-GIDIOX was asymptomatic elevation of transaminases (gr. 1-2 and 3-4 in 65,5% and 6,9% of courses respectively), while leukopenia gr. 4 occurred in 74,1% of courses (median 5 days, range 1-13), thrombocytopenia gr. 4 -39,7% courses. 45/47 patients underwent autoSCT: 28/29 in Arm1 and 17/18 in Arm2. The sources of stem cells were PBSC in 39/45 patients (86,7%) and BM in 6/45 (13,3%) patients with PBSC collection failure following R-HMA (3/28) or R-GIDIOX (3/17). With median follow-up of 31 months (range 11-76), the estimated 4-year OS and EFS remain identical in both groups: 78% (SE 12%) and 72% (SE 18%), respectively. Conclusions: Combination of R-DA-EPOCH/R-GIDIOX followed autoSCT and R-maintenance is well tolerated and produces EFS/OS similar to those seen with more toxic regimen utilizing R-HD-MTX-AraC. Equal outcomes were observed despite higher proportion of high risk patients treated with non-HD-AraC regimen. We conclude that R-GIDIOX can be an alternative component of induction regimen for those patient with MCL who are not candidates for intensification with high-dose AraC and MTX. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Choosing Optimal Firstline Helicobacter pylori Therapy: a View from a Region with High Rates of Antibiotic Resistance

Helicobacter pylori is a gram-negative, microaerophilic spiral bacillus that is associated with life-threatening diseases such as gastric cancer, gastric MALT lymphoma, and peptic ulcer disease. The definition of an effective therapy is one that achieves at least a 90% eradication rate on a per-protocol basis with the first attempt. Eradication rates of H. pylori have declined to unacceptable levels worldwide, mostly due to antibiotic resistance and standard triple therapy gradually has lost its efficacy in most counties. However, bismuth quadruple therapy, when prescribed properly, has maintained its effectiveness. Alternative first-line regimens such as sequential and concomitant therapy were developed to substitute for standard triple therapy and were highly effective in the countries where they were developed, but proved susceptible to failure in regions with high rates of antibiotic resistance. Antibiotic resistance rates in Russia are high, however there is lack of data regarding comparative efficacy of first-line eradication options. The authors of this review extrapolate the knowledge of H. pylori first-line eradication options in Russia based on data from other countries, as well as from domestic studies. The available data support use of 14-day regimens with concomitant therapy, bismuth quadruple therapy, or furazolidone quadruple therapy for empiric use in adults. In addition, 14-day levofloxacin-containing therapies could be used if resistance is relatively low or lacking as triple therapy or possibly as a 5-day concomitant levofloxacin therapy.

First-Line Combination Chemotherapy with Cisplatin, Etoposide and Ifosfamide for the Treatment of Disseminated Germ Cell Cancer: Re-Evaluation in the Granulocyte Colony-Stimulating Factor Era

Background: This study re-evaluated the efficacy and tolerability of cisplatin, etoposide, and ifosfamide (VIP) combination chemotherapy as an alternative first-line regimen for patients with disseminated germ cell cancer (GCC) in this granulocyte colony-stimulating factor (G-CSF) era. Methods: The medical records of 91 consecutive patients with previously untreated disseminated GCC who received first-line VIP between 1995 and 2011 were retrospectively reviewed. Results: The 5-year overall survival rates for patients with good (n = 49), intermediate (n = 22) and poor (n = 20) prognoses according to the International Germ Cell Cancer Collaborative Group classification were 100, 79 and 83%, respectively. G-CSF was given to all patients, and no treatment-related deaths due to myelosuppression occurred. Conclusion: The present study is the first to examine the therapeutic outcomes and safety profile of first-line VIP after routine G-CSF use. VIP might be an alternative first-line regimen for patients with disseminated GCC in this G-CSF era.

Pretreatment HIV-1 drug resistance in Africa

476 www.thelancet.com/infection Vol 13 June 2013 1 Hamers RL, Schuurman R, Sigaloff KCE, et al, for the PharmAccess African Studies to Evaluate Resistance (PASER) Investigators. Eff ect of pretreatment HIV-1 drug resistance on immunological, virological, and drugresistance outcomes of fi rst-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study. Lancet Infect Dis 2012;12: 307–17. 2 Lynen L, Fransen K, Van Griensven J, Colebunders R. Pretreatment HIV-1 drug resistance testing in sub-Saharan Africa. Lancet Infect Dis 2012; 12: 911. 3 Roberts T, Bygrave H, Fajardo E, Ford N. Challenges and opportunities for the implementation of virological testing in resource-limited settings. J Int AIDS Soc; 15: 17324. 4 Hamers RL, Sawyer AW, Tuohy M, Stevens WS, Rinke de Wit TF, Hill AM. Cost-eff ectiveness of laboratory monitoring for management of HIV treatment in sub-Saharan Africa: a model-based analysis. AIDS 2012; 26: 1663–72. 5 Sigaloff KC, Hamers RL, Wallis CL, et al. Unnecessary antiretroviral treatment switches and accumulation of HIV resistance mutations; two arguments for viral load monitoring in Africa. J Acquir Immune Defi c Syndr 2011; 58: 23–31. 6 Nichols BE, Sigaloff KC, Kityo C, et al. Benefi ts of early antiretroviral treatment initiation outweigh risk of transmitted HIV drug resistance: a modelling study of two east African settings. 20th Conference on Retroviruses and Opportunistic Infections; March 3–6, 2013; Atlanta, GA. Abstr 1116. 7 Phillips AN, Pillay D, Garnett G, et al. Eff ect on transmission of HIV-1 resistance of timing of implementation of viral load monitoring to determine switches from fi rst to second-line antiretroviral regimens in resource-limited settings. AIDS 2011; 25: 843–50. 8 Gupta RK, Jordan MR, Sultan BJ, et al. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis. Lancet 2012, 380: 1250–58. test ing and alternative fi rst-line regimens. Accurate ident ifi cation of virological failure will preserve drug options by avoiding the incremental cost of unnecessary switches and reducing drugresistance accumulation. Moreover, mathematical models predict that access to viral-load monitoring and second-line regimens might mitigate transmitted drug resistance. A shift to protease inhibitors in fi rst-line ART is regarded as a last resort by many experts, since this would have major programmatic implications, increase drug cost, and restrict options for constructing eff ective second-line regimens. Routine pretreatment drug-resistance testing is not feasible for most ART programmes because of restricted resources and laboratory capacity. As levels of transmitted drug resistance increase in east and southern Africa, we argue that improved functioning of national HIV treatment programmes will be crucial to preserve the longterm eff ectiveness of available ART regimens. Functioning would be improved by an uninterrupted drug supply, optimised patient adherence and retention, and access to viral-load monitoring.

Cost and Cost-Effectiveness of Switching From d4T or AZT to a TDF-Based First-Line Regimen in a Resource-Limited Setting in Rural Lesotho

Latest World Health Organization guidelines recommend shifting away from Stavudine (d4T)-based regimens due to severe side effects. However, widespread replacement of d4T by Tenofovir (TDF) or Zidovudine (AZT) is hampered by cost concerns. We established the cost-effectiveness of alternative first-line regimens using primary utilization, cost, and outcome data from a program in a rural district in Lesotho. We calculated cost per patient-year, incremental costs, and incremental cost-effectiveness ratios per life year, and per Quality Adjusted Life Year gained. Uncertainty was assessed using multiway and probabilistic sensitivity analyses. Our study included 1260 patients representing 1635 patient-years on antiretroviral therapy (ART). Six hundred eight patients were on TDF, 290 were on AZT, and 362 were on d4T. Patients on d4T experienced more toxicities; toxicities with the biggest impact on quality of life were moderate neuropathy and severe lipodystrophy. The cost per patient-year ranged from US $266 on d4T to US $353 on TDF. Inpatient care and essential drug costs were higher for patients on d4T than on AZT or TDF. Incremental cost-effectiveness ratio results suggest that AZT-based ART is weakly dominated by a combination of d4T- and TDF-based ART. This is one of the first analyses to investigate the cost-effectiveness of TDF using primary data in a resource-poor setting. Although TDF-based first-line ART is more costly than d4T, it is also more effective. Political pressure should be exerted to encourage further price reductions and additional generic manufacturing for TDF and partner drugs such as Efavirenz. This should be met by a commitment from donors and implementers to ensure that supply is met by a clear demand.

Antiretroviral treatment changes in adults from Côte d'Ivoire: the roles of tuberculosis and pregnancy

To determine the rates and causes of first antiretroviral treatment changes in HIV-infected adults in Côte d'Ivoire. We evaluated adults who initiated antiretroviral treatment in an outpatient clinic in Abidjan. We recorded baseline and follow-up data, including drug prescriptions and reasons for changing to alternative first-line regimens (drug substitution for any reason but failure) or second-line regimens (switch for failure). Two thousand and twelve HIV-infected adults (73% women) initiated antiretroviral treatment. At baseline, 9% of all patients were on treatment for tuberculosis and 3% of women were pregnant. First-line antiretroviral treatment consisted of two nucleoside reverse transcriptase inhibitors (58% stavudine-lamivudine, 42% zidovudine-lamivudine) and efavirenz (63%), nevirapine (32%) or indinavir (5%). Median follow-up time was 16.9 months. During this time, 205 (10%) patients died and 261 (13%) were lost to follow-up. Overall, the rate of treatment modifications was 20.7/100 patient-years. The most common modifications were drug substitutions for intolerance (12.4/100 patient-years), pregnancy (4.5/100 patient-years) and tuberculosis (2.5/100 patient-years). The rates of intolerance-related substitutions were 17.9/100 patient-years for stavudine, 6.3/100 patient-years for nevirapine, 3.9/100 patient-years for zidovudine and 0.1/100 patient-years for efavirenz. Twenty percent of efavirenz substitutions resulted from pregnancy and 18% of nevirapine substitutions were related to tuberculosis treatment. During the first months following antiretroviral treatment initiation, a third of all treatment changes occurred for reasons other than intolerance to the drug or treatment failure. In Africa, drug forecasting is crucial to ensuring the success of HIV treatment programmes. Drugs that do not require interruptions during pregnancy or tuberculosis treatment should be made more readily available as first-line drugs in sub-Saharan Africa.

Discontinuation of standard first‐line antiretroviral therapy in a cohort of 1434 Malawian children

The standard first-line antiretroviral (ART) regimen in Malawi for both adults and children is a fixed-dose combination tablet containing stavudine (d4T), lamivudine (3TC) and nevirapine (NVP). This regimen has been shown to yield satisfactory virologic and immunologic outcomes in children. Published studies have described insights into discontinuation of first-line regimen and toxicities of ART in adults, but similar studies in paediatric populations are lacking.A retrospective cohort study was undertaken to assess reasons for discontinuation of the standard first-line ART regimen (d4T/3TC/NVP) in a paediatric population. In total, 1434 patients met eligibility criteria and were included. The cohort had mean and median age at ART initiation of 4.7 years and 2.9 years, respectively (range: 0.1 months-18.7 years). The gender distribution was 47% female and 53% male. Median follow-up time on ART was 1.8 years (range: 2 weeks-3.9 years). A majority (96.2%) of patients were on the standard first-line ART regimen, while 3.8% (54) were on a different regimen. Twenty-eight patients (2.0%) were on an alternative first-line regimen due to toxicities, 22 patients (1.5%) were on a second-line regimen due to ART failure, and four patients (0.3%) were on a non-standard regimen for other clinical reasons.Of the 28 patients who experienced toxicities requiring ART regimen change, 60.7% (17) were caused by NVP, 39.3% (11) by d4T, and none by 3TC. The median time from first-line ART initiation to alternative first-line ART was two months (range: 10 days-28.1 months); 60.7% of patients on alternative first-line ART were male. Average time on ART until switch to second-line ART regimen was 16.3 months (SD: 9.3 months). The probability of failure after one year on first-line regimen was 1.6% (95% CI: 0.9-2.6).There was no compelling evidence in this cohort, representing approximately 10% of all children on ART in Malawi, to support changing the standard paediatric first-line regimen based on early toxicities or failure. However, experience from the national adult cohort, longer term follow up of the paediatric cohort in this study, emerging data on resistance after single-dose NVP containing mother to child transmission antiretroviral prophylaxis, and new 2009 World Health Organization ART recommendations may influence national policy change to a different first-line regimen.

Very early mortality in patients starting antiretroviral treatment at primary health centres in rural Malawi

To report on the cumulative proportion of deaths occurring within 3 months of starting antiretroviral treatment (ART) and to identify factors associated with such deaths, among adults at primary health centres in a rural district of Malawi. Retrospective cohort study: from June 2006 to April 2008, deaths occurring over a 3-month period were determined and risk factors examined. A total of 2316 adults (706 men and 1610 women; median age 35 years) were included in the analysis and followed up for a total of 1588 person-years (PY); 277 (12%) people died, of whom 206 (74%) people died within 3 months of initiating ART (cumulative incidence: 13.0; 95% confidence interval: 11.3-14.8 per 100 PY of follow-up). Significant risk factors associated with early deaths included male sex, WHO stage 4 disease, oesophageal or persistent oral candidiasis and unexplained presumed or measured weight loss >10%. One in every 3 patients who either died or was lost to follow up had unexplained weight loss >10%, and survival in this group was significantly different from patients without this condition. Seven in 10 individuals initiating ART at primary health centres die early. Specific groups of patients are at higher risk of such mortality and should receive priority attention, care and support.

Field-adapted sampling of whole blood to determine the levels of amodiaquine and its metabolite in children with uncomplicated malaria treated with amodiaquine plus artesunate combination

BackgroundArtemisinin combination therapy (ACT) has been widely adopted as first-line treatment for uncomplicated falciparum malaria. In Uganda, amodiaquine plus artesunate (AQ+AS), is the alternative first-line regimen to Coartem® (artemether + lumefantrine) for the treatment of uncomplicated falciparum malaria. Currently, there are few field-adapted analytical techniques for monitoring amodiaquine utilization in patients. This study evaluates the field applicability of a new method to determine amodiaquine and its metabolite concentrations in whole blood dried on filter paper.MethodsTwelve patients aged between 1.5 to 8 years with uncomplicated malaria received three standard oral doses of AQ+AS. Filter paper blood samples were collected before drug intake and at six different time points over 28 days period. A new field-adapted sampling procedure and liquid chromatographic method was used for quantitative determination of amodiaquine and its metabolite in whole blood.ResultsThe sampling procedure was successively applied in the field. Amodiaquine could be quantified for at least three days and the metabolite up to 28 days. All parasites in all the 12 patients cleared within the first three days of treatment and no adverse drug effects were observed.ConclusionThe methodology is suitable for field studies. The possibility to determine the concentration of the active metabolite of amodiaquine up to 28 days suggested that the method is sensitive enough to monitor amodiaquine utilization in patients. Amodiaquine plus artesunate seems effective for treatment of falciparum malaria.

Gemcitabine in bladder cancer

Gemcitabine, a deoxycytidine analogue, is an inhibitor of DNA synthesis. With myelosupression being its most serious toxicity, gemcitabine has, however, a favourable toxicity profile. It was tested in urothelial bladder cancer at different stages of the disease. In superficial Bacillus Calmette-GuÉrin (BCG)-resistant bladder cancer as well as in BCG-intolerant patients, intravesical gemcitabine instillation has demonstrated a significant activity. In the adjuvant setting, the combination of gemcitabine and cisplatin (GC) has proved to be a feasible protocol. In locally advanced and metastatic disease, GC is admitted as a standard alternative first-line regimen. Gemcitabine is also an interesting choice for unfit patients when used as a single treatment or in combination with other chemotherapeutic agents as carboplatin or taxanes. This article reviews most of the studies performed in order to promote the usefulness of gemcitabine in bladder cancer.

Options for first- and second-line therapy in small cell lung cancer — a workshop discussion

In a case study-based workshop, physicians were asked to discuss various aspects of patient management in small cell lung cancer (SCLC). For first-line chemotherapy, most investigators recommended treatment with etoposide/cisplatin, with possible dosing variations according to tolerability and convenience. In France (but not elsewhere), medical oncologists tend to use a four-drug regimen (etoposide/cisplatin/cyclophosphamide/epirubicin), based on the results of an extensive-stage SCLC trial. Alternative first-line regimens, such as vincristine/ifosfamide/carboplatin/etoposide (VICE) and topotecan/platinum, are currently being explored. Options for therapy in patients with recurrent disease are move varied, although there was consensus that active treatment at relapse should be considered. Regimens include topotecan (alone or in combination), cyclophosphamide/doxorubicin/vincristine (CAV) and re-induction with the earlier first-line agents. Studies are also investigating the potential benefits of other combinations, including topotecan/vinorelbine and paclitaxel/carboplatin. For patients with relapsed extensive-stage SCLC and brain metastases, whole brain radiation therapy was considered appropriate for both palliative and therapeutic reasons. The potential role of combination therapy with topotecan/temozolomide, both of which cross the blood-brain barrier, is currently being investigated.